Injury can initiate a painful process of nerve degeneration involving axons and their supporting Schwann cells (Wallerian degeneration) that is followed by a period of endoneurial remodeling resulting in axonal regeneration and remyelination. It is becoming increasingly clear that these two linked processes are orchestrated by neural-immune interactions controlling the activity of TNF-alpha (TNF). Wallerian degeneration is clearly mediated by TNF and its receptor TNFR1, and we have shown that it is related to the complex events that define the neuropathic pain state, events that include recruitment and activation of macrophages, and activation and apoptosis of Schwann cells. The progress report discusses new insights into the relationship between TNF and the matrix metalloproteinases (MMP) in terms of TNF sequestration and release, MMP activation, endoneurial remodeling, and TNF/TNFR1 retrograde axonal transport from the injury site to the spinal cord. In this application we propose to continue our work on the role of TNF in nerve degeneration, regeneration, and pain by focusing on the activity of the critical p38 mitogen-activated protein kinase (P38 MAPK), which is involved in MMP- and TNF-signaling. Preliminary data support our hypothesis that p38 inhibition increases the rate of axonal regeneration after painful nerve crush injury by protecting against Schwann cell apoptosis and expression of TNF. We also demonstrate in preliminary experiments that p38 inhibition reduces the hyperalgesia associated with Wallerian degeneration during the neuropathy caused by chronic constriction injury (CCI) of nerve. We propose a unifying hypothesis that links p38 inhibition with reduced nerve degeneration and enhanced regeneration via changes in MMP-9 activation and TNF activity. We propose to pursue this line of research by using rats and genetic strains of mice with TNF deficiencies, and by inhibiting p38 MAPK as an experimental tool to further understand neural-immune interactions and TNF signaling in painful neuropathy.